The number of people diagnosed as diabetic is increasing, due to insufficient exercise or a westernization of life style, such as a habit of eating a high fat diet. Diabetes which more than 90% of patients are suffering from are type II diabetes, characterized by a deficiency of insulin action caused by an increase of insulin resistance or a decrease of insulin secretion.
In a healthy person, when the blood glucose level is increased by food ingestion, insulin secreted from the pancreas is rapidly increased. In response to the resultant insulin concentration, an action of decreasing the glucose release in the liver and an action of increasing the glucose uptake in skeletal muscles and adipose tissues occur, and thus the blood glucose level is decreased and returns to the normal level. However, in a patient suffering from type II diabetes exhibiting an insulin resistance, due to a low sensibility to insulin in tissues, a decrease of the glucose release in the liver or an increase of the glucose uptake in muscles and adipose tissues in response to insulin is not sufficient, and thus abnormal changes in the blood glucose level, such as postprandial hyperglycemia or fasting hyperglycemia, is observed. After the developing of diabetes, the diabetes progresses without subjective symptoms for a long time. Because complications, such as diabetic retinopathy, diabetic nephropathy, or neuropathy, supervene in severe diabetes, it is very important to prevent or treat diabetes at an early stage.
As therapeutic agents for diabetes capable of alleviating insulin resistance, biguanides, which increase the action of inhibiting glucose release in the liver as the main effect, or thiazoline derivatives, which decrease the insulin resistance in the liver, fat, and/or skeletal muscles as the main effect, are clinically used. However, a cautious administration is required due to complications, side effects, or the like, and thus a more efficient agent exhibiting no side effects is desired for alleviating insulin resistance (non-patent reference 1).
The decreased insulin action to glucose metabolism is commonly observed in type II diabetes, and closely involved in abnormal glucose metabolism in the whole body. Therefore, a pathological clarification of type II diabetes and development of therapeutic agents therefor must clarify a mechanism of promoting glucose transport by insulin (non-patent reference 2). In other words, a factor which inhibits the glucose transport mechanism is probably involved in diabetes.
Insulin and insulin-like growth factor I (IGF-I) are peptide hormones belonging to the same family, and are highly similar in structure and functions. Further, the insulin receptor and IGF-I receptor are homologous molecules belonging to a tyrosine kinase-type receptor family, and each native ligand thereof exhibits a cross-reactivity for the other receptor (non-patent reference 3). It is known that a signal transduction is promoted by binding insulin or IGF-1 with the receptor thereof, and that a glucose uptake from extracellular fluid causes an action of decreasing blood glucose (non-patent reference 4). IGF-I alone is not stable in blood, and more than 90% thereof forms complexes with insulin-like growth factor binding protein (IGFBP), to maintain stability, and thus it is considered that the existence of IGFBP is important from the viewpoint of tissue delivery or control of the action (non-patent reference 5). Many reports on the relationship between diabetes and IGFBP have been made, and it is known, for example, that IGFBP-3 and IGFBP-5 are decreased in the blood of patients suffering from type I/II diabetes (non-patent reference 6), that an N-terminus undigested product (18 kDa) of IGFBP-3 is increased in the urine of patients suffering from type I diabetes (non-patent reference 7), that when streptozotocin, which specifically destroys pancreatic β cells and can cause diabetes by experimentally administering it to an animal, is administered to rat to induce diabetes, IGFBP-3 is expressed together with IGFBP-5 in renal glomeruli (non-patent reference 8), that a positive correlation between an activity of digesting IGFBP-3 in the urine of patients suffering from type II diabetes with diabetic nephropathy and an amount of albumin leaked into the urine of patients suffering from diabetic nephropathy is observed (non-patent reference 9), that a polymorphism of causes of type I diabetes exists near the IGFBP-2 and IGFBP-5 genes (non-patent reference 10), and that when IGFBP-3 is digested by protease, the affinity thereof for IGF-I is decreased and the affinity of the digested N-terminus fragment for insulin is increased (non-patent reference 11 and non-patent reference 12).
As described above, it is considered that an effective method for treating diabetes (alleviating insulin resistance) can be also provided by inhibiting IGFBP digestion.
In this connection, the deduced amino acid sequence of human ADAM8 is known, and it is suggested that human ADAM8 is metalloprotease and is involved in tumors and platelet aggregation (patent reference 1, patent reference 2, non-patent reference 13, non-patent reference 14, and non-patent reference 15). However, a relationship between human ADAM8 and diabetes is not suggested.    (non-patent reference 1) Ryuzo Kawamori et al., “Tonyoubyou 2001 Karada no Kagaku, zoukan (supplement)”, Nippon-Hyoron-sha, 2001, p. 86–108    (non-patent reference 2) Oka, “Saishin Igaku (The Medical Frontline)”, 2002, p. 41–46    (non-patent reference 3) Miyazono et al., “Saitokain & zoshoku Inshi (Cytokines and growth factors)”, YODOSHA, 104–109, 1998    (non-patent reference 4) Kadowaki et al., “Medical terms libraly, diabetes”, YODOSHA, 52–53, 1995    (non-patent reference 5) Yamanaka et al., “Horumon to Rinsho (CLINCAL ENDOCRINOLOGY)”, 29–38, 1998    (non-patent reference 6) J. Endocrinol., 159, 297–306, 1998    (non-patent reference 7) Clinical Endocrinology, 51, 587–596, 1999    (non-patent reference 8) Am. J. Kidney. diseases, 1000–1010, 1998    (non-patent reference 9) J. Clin. Endo. Metab., 85, 1163–1169, 2000    (non-patent reference 10) Science, 272, 1811–1813, 1996    (non-patent reference 11) Yamanaka Y. et al., J. Biol. Chem., 272, 30729–30734, 1997    (non-patent reference 12) Peter V. et al., J. Clin. Endocrinol. Metab., 83, 1392–1395,1998    (non-patent reference 13) SWISSPROT P78325 ADO8 HUMAN(1997.11.1) available on the Internet at kr.expasy.org/cgi-bin/niceprot.pl?P78325    (non-patent reference 14) NCBI D26579 1 Homo sapiens mRNA (1999.2.6) available on the Internet at ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&d b=nucleotide&list_uids=l864004&dopt=GenBank    (non-patent reference 15) Genomics 1997 Apr. 1 41, 56 CD156 (human ADAM8)    (patent reference 1) WO01/09189    (patent reference 2) WO01/53486